cancer cells outcompete macrophages for microenvironmental zinc to drive immunotherapy resistance.

Approximately 50% of cancers exhibit decreased expression ( ), which is linked to immune checkpoint blockade (ICB) resistance. While is traditionally recognized as a tumor suppressor and cell cycle regulator, we have previously put forth a new paradigm demonstrating its role in intracellular metabolic reprogramming. Whether the metabolic derangement due to loss alters metabolites within the tumor microenvironment (TME) and how that affects the immune compartment and ICB response has never been investigated.

Dysfunctional KLRB1CD8 T-cell responses are generated in chronically inflamed systemic sclerosis skin.

Objectives: To analyse the immune mechanisms of diffuse cutaneous systemic sclerosis (dcSSc) skin disease focusing on CD8 T-cell responses in the affected skin of patients because chronic inflammation, vasculopathy, and extensive cutaneous fibrosis are prominent features of dcSSc skin disease, causing pain and disability in patients, with no effective therapy.

Methods: Single-cell transcriptomics and epigenomics were applied to well-characterised patient skin samples to identify transcriptomes and key regulators of skin-resident CD8 T-cell subsets. Multicolor immunofluorescence miscoscopy was used to validate molecular findings.

The survival of B cells is compromised in kidney disease.

Antibody-mediated protection against pathogens is crucial to a healthy life. However, the recent SARS-CoV-2 pandemic has shown that pre-existing comorbid conditions including kidney disease account for compromised humoral immunity to infections. Individuals with kidney disease are not only susceptible to infections but also exhibit poor vaccine-induced antibody response.

Agonism of the glutamate receptor GluK2 suppresses dermal mast cell activation and cutaneous inflammation.

Activation of dermal mast cells through the Mas-related G protein-coupled receptor B2 receptor (MrgprB2 in mice and MrgprX2 in humans) is a key component of numerous inflammatory skin diseases, including dermatitis and rosacea. Sensory neurons actively suppress mast cell activation through the regulated release of glutamate, resulting in reduced expression of as well as genes associated with proteins found in mast cell granules. To determine whether exogenous glutamate receptor agonism could suppress mast cell function, we determined that mast cells have relatively selective expression of the glutamate receptor ionotropic, kainate 2 (GluK2).

Altered AP-1, RUNX and EGR chromatin dynamics drive fibrotic lung disease.

Pulmonary fibrosis, including systemic sclerosis-associated interstitial lung disease (SSc-ILD), involves myofibroblasts and SPP1 macrophages as drivers of fibrosis. Single-cell RNA sequencing has delineated fibroblast and macrophages transcriptomes, but limited insight into transcriptional control of profibrotic gene programs. To address this challenge, we analyzed multiomic snATAC/snRNA-seq on explanted SSc-ILD and donor control lungs.

Private sector tuberculosis care quality during the COVID-19 pandemic: a repeated cross-sectional standardised patients study of adherence to national TB guidelines in urban Nigeria.

Only a third of tuberculosis (TB) cases in Nigeria in 2020 were diagnosed and notified, in part due to low detection and under-reporting from the private health sector. Using a standardised patient (SP) survey approach, we assessed how management of presumptive TB in the private sector aligns with national guidelines and whether this differed from a study conducted before the start of the COVID-19 pandemic. 13 SPs presented a presumptive TB case to 511 private providers in urban areas of Lagos and Kano states in May and June 2021.

Exploring online public survey lifestyle datasets with statistical analysis, machine learning and semantic ontology.

Lifestyle diseases significantly contribute to the global health burden, with lifestyle factors playing a crucial role in the development of depression. The COVID-19 pandemic has intensified many determinants of depression. This study aimed to identify lifestyle and demographic factors associated with depression symptoms among Indians during the pandemic, focusing on a sample from Kolkata, India.

Interpretable machine learning uncovers epithelial transcriptional rewiring and a role for Gelsolin in COPD.

Transcriptomic analyses have advanced the understanding of complex disease pathophysiology including chronic obstructive pulmonary disease (COPD). However, identifying relevant biologic causative factors has been limited by the integration of high dimensionality data. COPD is characterized by lung destruction and inflammation, with smoke exposure being a major risk factor.

Tim-3 Is Required for Regulatory T Cell-Mediated Promotion of T Cell Exhaustion and Viral Persistence during Chronic Lymphocytic Choriomeningitis Virus Infection.

Expression of T cell Ig and mucin domain-containing protein 3 (Tim-3) is upregulated on regulatory T cells (Tregs) during chronic viral infections. In several murine and human chronic infections, the expression of Tim-3 is associated with poor control of viral burden and impaired antiviral immune responses. However, the role of Tim-3+ Tregs during persistent viral infections has not been fully defined.

Deep humoral profiling coupled to interpretable machine learning unveils diagnostic markers and pathophysiology of schistosomiasis.

Schistosomiasis, a highly prevalent parasitic disease, affects more than 200 million people worldwide. Current diagnostics based on parasite egg detection in stool detect infection only at a late stage, and current antibody-based tests cannot distinguish past from current infection. Here, we developed and used a multiplexed antibody profiling platform to obtain a comprehensive repertoire of antihelminth humoral profiles including isotype, subclass, Fc receptor (FcR) binding, and glycosylation profiles of antigen-specific antibodies.

Aberrant mitochondrial DNA synthesis in macrophages exacerbates inflammation and atherosclerosis.

There is a large body of evidence that cellular metabolism governs inflammation, and that inflammation contributes to the progression of atherosclerosis. However, whether mitochondrial DNA synthesis affects macrophage function and atherosclerosis pathology is not fully understood. Here we show, by transcriptomic analyzes of plaque macrophages, spatial single cell transcriptomics of atherosclerotic plaques, and functional experiments, that mitochondrial DNA (mtDNA) synthesis in atherosclerotic plaque macrophages are triggered by vascular cell adhesion molecule 1 (VCAM-1) under inflammatory conditions in both humans and mice.

The RNA binding protein Arid5a drives IL-17-dependent autoantibody-induced glomerulonephritis.

Autoantibody-mediated glomerulonephritis (AGN) arises from dysregulated renal inflammation, with urgent need for improved treatments. IL-17 is implicated in AGN and drives pathology in a kidney-intrinsic manner via renal tubular epithelial cells (RTECs). Nonetheless, downstream signaling mechanisms provoking kidney pathology are poorly understood.

Mapping the Evolutionary Space of SARS-CoV-2 Variants to Anticipate Emergence of Subvariants Resistant to COVID-19 Therapeutics.

New sublineages of SARS-CoV-2 variants-of-concern (VOCs) continuously emerge with mutations in the spike glycoprotein. In most cases, the sublineage-defining mutations vary between the VOCs. It is unclear whether these differences reflect lineage-specific likelihoods for mutations at each spike position or the stochastic nature of their appearance.

The medical competence of health care providers in sub-Saharan Africa: Evidence from 16 127 providers across 11 countries.

Despite a consensus that quality of care is critically deficient in low-income countries, few nationally representative studies provide comparable measures of quality of care across countries. To address this gap, we used nationally representative data from in-person administrations of clinical vignettes to measure the competence of 16 127 health care providers across 11 sub-Saharan African countries. Rather than large variations across countries, we found that 81% of the variation in competence is within countries and the characteristics of health care providers do not explain most of this variation.

Sliding Window INteraction Grammar (SWING): a generalized interaction language model for peptide and protein interactions.

The explosion of sequence data has allowed the rapid growth of protein language models (pLMs). pLMs have now been employed in many frameworks including variant-effect and peptide-specificity prediction. Traditionally, for protein-protein or peptide-protein interactions (PPIs), corresponding sequences are either co-embedded followed by post-hoc integration or the sequences are concatenated prior to embedding.

Temporal dynamics and genomic programming of plasma cell fates.

Affinity-matured plasma cells (PCs) of varying lifespans are generated through a germinal center (GC) response. The developmental dynamics and genomic programs of antigen-specific PC precursors remain to be elucidated. Here, using a model antigen in mice, we demonstrate biphasic generation of PC precursors, with those generating long-lived bone marrow PCs preferentially produced in the late phase of GC response.

Prevalence of long COVID symptoms in Haryana, India: a cross-sectional follow-up study.

Background: Emerging research indicates growing concern over long COVID globally, although there have been limited studies that estimate population burden. We aimed to estimate the burden of long COVID in three districts of Haryana, India, using an opportunity to link a seroprevalence study to follow-up survey of symptoms associated with long COVID.

Methods: We used a population-based seroprevalence survey for COVID-19 conducted in September 2021 across Haryana, India.